Abstract 26: Transient Limb Ischemia Induces Remote Postconditioning in Humans by a KATP Channel-Dependent Mechanism
Background: Intermittent restoration of blood flow after prolonged (index) ischemia to the myocardium reduces ischemia-reperfusion injury (IRI), so-called postconditioning (PostC). PostC causes a similar degree of protection to ischemic preconditioning (IPC; brief periods of ischemia before index ischemia), suggesting that much of the injury due to IR is sustained during early reperfusion. Recent animal studies have demonstrated that protection from IRI can be achieved by an ischemic conditioning stimulus applied at a remote site co-temporaneously with index ischemia to the myocardium (remote PostC; RPostC). Using an in vivo model of endothelial IRI, we sought to determine if RPostC occurred in humans and whether protection was dependent on activation of ATP-sensitive potassium (KATP) channels.
Methods: Endothelial function was assessed by flow-mediated dilation (FMD) before and after IR (20 min. of arm ischemia followed by reperfusion) in healthy volunteers. RPostC was induced by 2 cycles of 5 min. ischemia and reperfusion applied on the contralateral leg during the 20-min. ischemic insult on the arm. In order to determine the dependence of RPostC on KATP channels, the RPostC stimulus was applied in the presence of the KATP channel blocker glibenclamide (5mg), administered orally sixty minutes prior to baseline FMD. To exclude any direct effects of glibenclamide on the endothelial response to IR, FMD was measured before and after IR in the presence of systemic glibenclamide. FMD (percentage change from baseline diameter) was expressed as mean±SEM and compared by ANOVA.
Results: IR alone caused a significant reduction in FMD after 20 minutes of reperfusion (9.2±1.0% pre-IR; 3.6±0.7% post-IR, p<0.001; n=9). This reduction was prevented by RPostC (9.2±1.1% pre-IR; 8.1±1.0% post-IR, NS; n=9). Systemic glibenclamide blocked the protective effects of RPostC (8.6±0.5% pre-IR; 2.8±0.8% post-IR, p<0.01; n=7) but had no direct effect on the endothelial response to IR (7.8±0.6% pre-IR; 2.5±0.4% post-IR, p<0.001; n=5).
Conclusions: RPostC prevents endothelial IRI in humans by activating KATP channels, and raises the possibility that it could be tested in patients presenting with acute ischemia about to undergo spontaneous or therapeutic reperfusion.